Testing density-dependence and path-dependence in long-term population dynamics under differentiated local contexts contributes to delineate the changing role of socioeconomic forces at the base of regional disparities. Despite a millenary settlement history, such issue has been rarely investigated in Europe, and especially in highly divided countries such as those in the Mediterranean region. Using econometric modeling to manage spatial heterogeneity, our study verifies the role of selected drivers of population growth at ten times between 1921 and 2021 in more than 8000 Italian municipalities verifying density-dependent and path-dependent dynamics. Results of global and quantile (spatial) regressions highlight a differential impact of density and (lagged) population growth on demographic dynamics along the urban cycle in Italy. Being weakly significant in the inter-war period (1921–1951), econometric models totalized a high goodness-of-fit in correspondence with compact urbanization (1951–1981). Model’s fit declined in the following decades (1981–2021) reflecting suburbanization and counter-urbanization. Density-dependence and path-dependence were found significant and, respectively, positive or negative, with compact urbanization, and much less intense with suburbanization and counter-urbanization. A spatial econometric investigation of density-dependent and path-dependent mechanisms of population dynamics provided an original explanation of metropolitan cycles, delineating the evolution of socioeconomic (local) systems along the urban-rural gradient.